DE102005005446A1

DE102005005446A1 - Unbreakable dosage forms with delayed release

Info

Publication number: DE102005005446A1
Application number: DE200510005446
Authority: DE
Inventors: Elisabeth Dr. Arkenau; Judy Dr. Ashworth; Johannes Dr. Bartholomäus
Original assignee: Grunenthal GmbH
Current assignee: Grunenthal GmbH
Priority date: 2005-02-04
Filing date: 2005-02-04
Publication date: 2006-08-10
Also published as: DK2478896T3; US20140112984A1; US20150374630A1; US10058548B2; US20160120810A1; KR101299928B1; ES2651016T3; RU2399371C2; US20170312271A1; WO2006082099A1; JP2008528654A; EP1845956A1; US20080311187A1; ES2629303T3; RU2461381C2; KR20070111510A; EP2478896B1; US20100151028A1; US20170209379A1; CN101175482B

Abstract

The invention relates to a dosage form comprising a physiologically active substance (A) with at least partially retarded release; optionally one or more physiologically acceptable auxiliary substances (B); and a synthetic or natural polymer (C); wherein the dosage form exhibits a breaking strength of at least 400 N.

Description

The present invention relates to a dosage form for administering a physiologically active substance (A), wherein the dosage form is mechanically stabilized, so that it can be crushed very difficult with conventional methods, such as hammers, milling, mortars, etc., do not, or at least , The substance (A) is released from the dosage form according to the invention under physiological conditions with an at least partially retarded profile.

Many physiologically active substances, such as food supplements, drugs, etc. are provided as sustained release formulations, that is in contrast to conventional formulations (eg so-called. "Immediate release" formulations), the substances from these formulations delayed over a comparatively long period of time, often is several hours, delivered to the body. The release of the substance from the dosage form on the one hand and a metabolism and excretion by the body on the other hand ensure a relatively uniform blood plasma level of the administered substance. As a result, the number of taken per day dosage units can be reduced frequently to the patient intake often being only once or twice a day required.

Sustained-release formulations may also reduce the extent of side effects of the substance in certain cases. So for example, some drugs more adverse reactions when at least temporarily a certain threshold concentration of the drug is exceeded in blood plasma. Such drugs are thus largely unsuitable for "immediate release" formulations, in particular when only two or three times daily administration is desired. Such drugs are therefore typically administered as sustained-release formulations, thus ensuring a continuous release of the active substance and the short-term exposure to high concentrations are prevented.

When sustained-release formulations of the physiologically active substance either in a release is typically controlled matrix embedded and / or the dosage form is coated with a film which controls the release.

However, especially elderly patients often have difficulties in taking solid dosage forms such as tablets, capsules, etc. They choke them and sometimes develop pronounced aversion to such dosage forms.

To address this problem, various apparatuses have been developed can be crushed with the help of solid dosage forms or pulverized ( "tablet crusher"). The use of such equipment for example, by the nursing staff in nursing homes. The dependents, the dosage forms are then administered not as a tablet, etc., but as a powder, for example, to bypass the difficulties in swallowing tablets.

The problem with such equipment, the crushing of the dosage forms, however, if it is in the dosage forms are delayed-release formulations. The comminution leads namely usually means that the internal structure of the dosage form, which is responsible for the sustained release, will be destroyed, whereby the retarding effect will be canceled. As a result of comminution, the diffusion paths of the physiologically active substances contained therein are shortened and / or the diffusion barrier removed. Thus, a sustained-release formulation in which the delayed release by means of a film coating is to be achieved after reduction only on a small percentage of their solid surface the film coating on. As a result, the total in the dosage form after administration often originally contained physiologically active substance in a relatively short time released, making leaps and bounds for a relatively short period of time a comparatively very high plasma concentration of the substance is achieved. From the original slow-release formulations are thus "immediate release" formulations.

However, depending on the physiological activity of the substance, this can cause serious side effects, leading in extreme cases even to the death of the patient. Examples of substances with such a hazard potential are antiparkinson agents, antiepileptic agents, antidiabetics, antihypertensives, antiarrhythmics, etc.

As a rule, these are dangers to persons who crush the dosage forms for themselves or for others, not consciously. It became known deaths of patients who are likely due to pulverization of sustained-release formulations by nurses or carers. For further details, for example, on JE Mitchell, Oral Dosage Forms That Should Not Be Crushed: 2000 update. Hospital Pharmacy, 2000; . H. Miller et al, To Crush or Not to Crush, Nursing 2000; . R. Grittith et al, Tablet Crushing and the law: the implications for nursing; Prof. Nurse 2003; and JG Schier et al Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. be referred Pharmacotherapy of 2003.

Even in infants sustained-release formulations can cause problems. So children can not distinguish them from sweets often solid dosage forms. For the children of such dosage forms, for example, because their parents this carelessness in the home have released into the environment, there is a risk that the children keep the forms for sweets and put them in your mouth and chew. Is this to sustained-release formulations containing a drug in a dosage that is intended for an adult, there is in such a case the child already contained the greater amount of drug the risk of overdose. By chewing the dosage form and the consequent cancellation of the delayed action, this risk is, however, exacerbated because the already anyway too high a dose of the additional release also within a much shorter time interval, which would already make for an adult significant dangers , for a child but more can have drastic consequences.

Chewing sustained-release formulations can lead to an overdose of the substance contained in adults. So chew adults, the dosage forms sometimes deliberately, as they are - often unaware of the nature and purpose of a sustained-release formulation - of which promise a quicker effect.

One known way to reduce the dangers posed by a comminution of the sustained-release formulations, is to provide the dosage form antagonists, ie, antidote, or compounds which cause a physiological defense reactions to add, wherein the physiological effect of these additives possible only unfolds when the dosage form was crushed prior to administration. However, this method has the advantage that the physiologically active substance is administered in yet nichtretardierter shape and that the organism or additionally loaded with another physiologically active substance, such as an antidote a defense reaction, such as emesis, triggers the disadvantage.

may be, there is a need for pharmaceutical dosage forms with delayed release, that reduce the risk of overdose, so that no antidote etc..

The invention is thus based on the object to provide a dosage form which releases a physiologically active substance retarded, however, reduces the risk of overdose, particularly as a result of improper handling of the dosage form, such as chewing, grinding in a mortar etc..

It has surprisingly been found that this object is achieved by a dosage form comprising

- a physiologically active substance (A) with at least partially retarded release (= component (A));
- optionally one or more physiologically acceptable auxiliary substances (B) (= component (B)); and
- a synthetic or natural polymer (C) (= component (C));

wherein the dosage form exhibits a breaking strength of at least 400 N.

The dosage form according to the invention optionally comprises over a wide temperature range, mechanical strength, in addition to the breaking strength and sufficient hardness and impact strength, so they are not crushed practically by chewing, mortars, hammering, etc. and also commercially available with the aid of apparatus for pulverizing conventional dosage forms or can be pulverized. Here, this is not necessarily achieved by the hardness of the dosage form. Thus, in particular also perform their impact resistance to the fact that the dosage form of the invention can indeed deform due to a mechanical action from outside, for meadow using a hammer, however it does not disintegrate into multiple fragments. A comminution is not possible even if the dosage form to increase its brittleness is first cooled, for example to temperatures below -25 ° C, -40 ° C or about in liquid nitrogen.

As a result, the sustained release is maintained and an overdose due to improper handling of the dosage form is effectively prevented.

Under delayed release is understood according to the invention preferably has a release profile in which the physiologically active substance is released with the aim of a prolonged therapeutic action over a longer period at reduced frequency of intake. This is achieved in particular when administered orally. The expression "with at least partially retarded release" according to the invention comprises any dosage forms which provide a modified release of the physiologically active substances contained therein. The dosage forms are preferably coated or uncoated dosage forms which are produced using special excipients, according to particular methods or by a combination of both options to modify the release rate or location of release specifically. With regard to the timing of the release of the following types are included in the dosage forms ertindungsgemäßen: delayed release (extended release, delayed release), repeat action release (repeat action release), sustained release (prolonged release) and sustained release (sustained release). For further details, for example, can be made to KH Bauer, Textbook of Pharmaceutical Technology, 6th edition, WVG Stuttgart., 1999

In a preferred embodiment the dosage form according to the invention under physiological conditions after 5 hours of not more than 99%, more preferably at most 90%, more preferably at most 75%, more preferably at most 50%, most preferably at most 40% and in particular at most 30% of the substance (A) free , It is particularly preferred that the dosage form in this case, neither tramadol hydrochloride, nor oxycodone hydrochloride, more preferably no opioid [N02A] (for the meaning of "N02A" see below). The release is preferably determined according to the standardized method in the European Pharmacopoeia, preferably under the conditions given in Example 1 conditions.

Through the use of certain polymers in an appropriate quantity and under appropriate conditions that the dosage form exhibits a breaking strength of at least 400 N, preferably at least 500 N is achieved according to the invention, (measured as stated in the description). This is to prevent a crushing, such as a pulverizing the dosage form by conventional means effectively manage.

Under a crusher according to the invention, the pulverization of the dosage form by application of force with conventional means, such. B. mortar and pestle, hammer, mallet or other usual means for pulverisation, in particular specially designed devices (tablet crusher) understood, wherein an optionally incurred fine fraction (particle size less than 0.3 mm or equal to) of 5 wt .-% non- may be exceeded.

The dosage form according to the invention is therefore suitable for preventing overdose of physiologically active substances, in particular of food supplements and drugs, which are provided in sustained release formulations. On antidotes, irritants, etc. can be dispensed with. In addition to preventing overdoses and the associated risks to the patient dosage forms according to the invention also ensure that the other advantages of sustained-release formulation, such as a uniform release over a longer period, are preserved and can not be removed easily.

To achieve the necessary breaking strength of the dosage form according to the invention at least one synthetic or natural polymer (C) is used, which contributes significantly to the increased breaking strength of the dosage form. The breaking strength of the dosage form is at least 400 N, the breaking strength is determined according to the method given in the description. In a preferred embodiment, the breaking strength of the dosage form is at least 500 N, preferably at least 600 N, preferably at least 700 N, more preferably at least 800 N, more preferably at least 900 N, most preferably at least 1000 N and particularly at least 1100 N.

Preferably, the dosage form of the invention contains at least one polymer (C) is selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; Polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly (hydroxyfatty acids), such as. B. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol ^®), poly (hydroxyvaleric acid), polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polyacetal (eg polysaccharides optionally (with modified side chains), Polylactidglykolid, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymer of polyethylene glycol and polybutylene terephthalate (Polyactive ^®), polyanhydride polifeprosan), copolymers thereof, and mixtures of at least two of said polymers.

high molecular weight thermoplastic polyalkylene oxides are preferred. Particularly preferred are high molecular weight polyethylene oxides with a preferably weight average molecular weight _(Mw) or viscosity average molecular weight (M _η) of at least 0.5 10 ⁶ g / mol, preferably at least 1.0 10 ⁶ g / mol, more preferably at least 2.5 10 ⁶ g / mol, more preferably at least 5.0 x 10 ⁶ g / mol, most preferably at least 7.5 10 ⁵ g / mol and in particular at least 10 10 ⁶ g / mol, preferably from 1.0 to 15 10 ⁶ g / mol. The skilled worker is aware of suitable methods, such as M _w and M _η can be determined. Preferably, the determination of M _η by rheological measurements and the determination of _Mw by gel permeation chromatography (GPC) at appropriate phases.

The polymers (C) have at 25 ° C preferably has a viscosity from 4,500 to 17,600 cP, measured in a 5 wt .-% aqueous solution using a Brookfield viscometer, Model RVF (spindle no. 2 / rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt .-% aqueous solution using the stated viscosimeter (spindle no. 1 or 3 / rotational speed 10 rpm) or 1,650 to 10,000 cP, measured on a 1 wt .-% aqueous solution using the stated viscosimeter (spindle no. 2 / rotational speed 2 rpm).

The polymer (C) is preferably used as a powder. It may be soluble in water.

Preferably, the polymer (C) in an amount of at least 20 wt .-%, more preferably at least 30 wt .-%, more preferably at least 40 wt .-%, most preferably at least 50 wt .-% and in particular at least 60 weight %, based on the total weight of the dosage form.

The dosage form according to the invention is suitable for the administration of more physiologically active substances (A) in a dosage form. Preferably, the dosage form is obtained only a certain physiologically active substance (A), preferably a food supplement or a drug (= active pharmaceutical ingredient).

In a preferred embodiment, the inventive dosage form contains no psychotropic active substances. The skilled worker knows which substances have a psychotropic effect. have commonly substances that influence mental processes, a psychotropic effect, ie a specific effect on mental functions. Substances with a psychotropic action may thus influence mood, either raising or lowering it. For purposes of description include in particular opioids, stimulants, tranquilizers (barbiturates and benzodiazepines) and other narcotics substances with a psychotropic action. It is preferable that effect (in particular with the intention of abuse) one with respect to the intended oral administration accelerated rise in level of the active ingredient with the desired of an abuser result for substances with a psychotropic action substances which especially at non-intended route of administration, namely, the kick , This kick can be achieved, for example, if the powdered dosage form is administered nasally, ie is sniffed. Preferred are substances with a psychotropic action such substances which human intellect and / or sensory perception influenced (with appropriate dosage, dosage form and Darreichungsart) in such a way that they are in principle suited to abuse.

The following opioids, tranquilizers or other drugs are substances with a psychotropic action and are therefore erfindungemäß not preferred in the dosage form include: alfentanil, Allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, Amfetaminil, amobarbital, anileridine, apocodeine, barbital, Bemidon, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, Butobarbital, butorphanol, camazepam, carfentanil, cathine / D-norpseudoephedrine, chlordiazepoxide, clobazam, Clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, Dimephetamol, dimethylthiambutene, dioxaphetyl, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, Fencamfamin, fenetylline, Fenpipramid, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, Haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphan, Levoxemacin, lofentanil , loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, Metapon, meptazinol, metazocine, methyl morphine, metamfetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil , morphine, myrophine, nabilone, Nalbuphen, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum, pemoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pholcodeine, Phenm etrazin, phenobarbital, phentermine, pinazepam, Pipradrol, piritramide, Prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, BUTABARBITAL, secobarbital, sufentanil, temazepam, tetrazepam, tilidine (cis and trans)), tramadol, triazolam, vinylbital, N- (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) propionamide, (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1R, 2R, 4S) -2- [dimethylamino) methyl-4- (p-fluorobenzyloxy) -1- (m-methoxyphenyl) cyclohexanol, (1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, (1S, 2S) -3 (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, preferably as racemate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl 2- (4-isobutyl-phenyl) -propionate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl 2- (6-methoxy-naphthalen-2-yl) -xpropionat, 3- (2-dimethylaminomethyl-cyclohex -phen -1-enyl) yl 2- (4-isobutyl-phenyl) -propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl) - phenyl 2- (6-methoxy-naphthalen-2-yl) propionate, (RR-SS) - 2-acetoxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1- hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -4-chloro-2-hydroxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy- 4-methyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methoxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-5-nitro-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2 ', 4'-difluoro -3-hydroxy-biphenyl-4-carboxylic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester and corresponding stereoisomeric compounds, in each case corresponding derivatives thereof, physiologically acceptable enantiomers, Ster eoisomere, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides, and in each case the physiologically acceptable compounds, in particular salts and solvates thereof, particularly preferably hydrochlorides.

Particularly preferably, the inventive dosage form contains no substance selected from the group consisting of opioids [A07DA, N01AH, N02A, R05DA, R05FA,], barbiturates [N01AF, N01AG, N03AA] benzodiazepine derivatives [N03AE], agents for the treatment of opiate addiction [ N07BC], anxiolytics [N05B], hypnotics and sedatives [N05C], psychostimulants, agents for the treatment of attention deficit / hyperactivity disorder (ADHD) and nootropics [N06B], antiemetics [A04A]; antiobesity excluding diet [A08A], centrally acting muscle relaxants [M03B ], and antidotes [V03AB]. The names given in square brackets correspond to as used by the WHO for the classification of drugs to the ATC index (preferably, as of January 2005). For further details on the ATC Index, for example, be made to U. Fricke, J. Gunther, Anatomical Therapeutic Chemical Classification with daily doses for the German pharmaceutical market: methodology of the ATC classification and DDD down. ATC Index with DDD information, Scientific Institute of the AOK; and Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, CRC Press; 18th edition (January 31, 2004).

In a preferred embodiment the dosage form according to the invention does not contain the nasal passages and / or pharynx substances, ie substances which cause when applied via the nasal passages and / or pharynx a physical reaction which is either so unpleasant for the patient that he will not continue administration, or may, for example burning, or physiologically counteracts manner taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. Further examples of the nasal passages and / or pharynx which substances are those substances which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the amounts to be used are commonly known in the art. So some of the nasal passages and / or pharynx substances based on one or more constituents or one or more plant parts of a Schartmann substance drug. Corresponding hot substance drugs are known to those skilled in the art and, for example, in "Pharmaceutical Biology - drugs and their ingredients" by Prof. Dr. described Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq.,. The corresponding description is hereby introduced as a reference and is deemed part of the disclosure.

Further, the dosage form according to the invention preferably contains no antagonists for the physiologically active substance (A), preferably no antagonists against psychotropic substances, in particular no antagonists of opioids. For a given physiologically active substance (A) suitable antagonists are known in the art and can be used as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Preferably, the inventive dosage form contains no antagonists selected from the group comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; and no neuroleptic, for example a compound selected from the group comprising haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, Chlorprotheaxin, Zucklopantexol, Flupentexol, Prithipendyl, zotepine, Penperidol, Pipanneron, Melperol and bromperidol.

In addition, the dosage form preferably contains no emetic. Emetics are known in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Preferably, the inventive dosage form contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as described for example in "Pharmazeutische Biologie - drugs and their ingredients" by Prof. Dr. Hildebert Wagner; 2. , revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982.. the corresponding literature description is hereby incorporated by reference and forms part of the disclosure. Preferably, the dosage form contains no apomorphine as an emetic.

Finally, the dosage form of the invention preferably also contains no bitter substance. Bitters and effective for use as the US-2003/0064099 A1 can be found in whose corresponding disclosure should be deemed as disclosure of the present application and is hereby incorporated by reference. Examples of bitter substances are aromatic oils such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit flavors, flavors of lemons, oranges, limes, grapefruit or mixtures thereof, and / or denatonium benzoate.

Thus, preferably the dosage form does not contain any substances with a psychotropic action, nor the nose and / or throat irritants, nor antagonists for the physiologically active substance (A), nor emetics, nor bitter substances.

In a preferred embodiment, the dosage form of the invention contains as a physiologically active substance (A) is a dietary supplement. Dietary supplements preferably contain one or more nutrients in concentrated, dose atypical of foodstuffs form.

They are intended to supplement the daily food in those cases in which a supply of food is inadequate or supplementation is desired. Preferably, the dietary supplement is selected from the group consisting of vitamins, minerals, trace elements, enzymes, fatty acids, amino acids, and antioxidants. Particularly preferred supplements are vitamins, provitamins and derivatives thereof, in particular retinol, Calcitriol, tocopherol, phylloquinone, thiamine, riboflavin, folic acid, niacin (in particular nicotinamide), pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin, biotin, and carotenoids.

In a preferred embodiment, the dosage form of the invention contains as a physiologically active substance (A) is a drug (= active pharmaceutical ingredient) which confers application of the dosage form as a drug and cause for their effectiveness. As drugs all known drugs used in the inventive dosage form principle in question, wherein the drugs as such, in the form of their derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their corresponding salts or solvates thereof, as racemates or may be one or more stereoisomers in the inventive dosage form in enriched form.

Particularly preferably, the inventive dosage form contains a substance (A) or more substances (A) selected from the group consisting of

- agents for the treatment and prevention of diseases of the alimentary system and metabolism [A]; in particular in stomatology [A01], agents for the treatment and prevention of acid-related disorders [A02], agents for the treatment and prevention of functional gastrointestinal disorders [A03], serotonin 5HT 3 antagonists [A04AA], antihistamines preparations [A04AB], means for bile and liver therapy [A05], laxatives [A06], Intestinal anti-infectives [A07A] Intestinal adsorbents [A07B], electrolytes with carbohydrates [A07C] Intestinal anti-inflammatory drugs [A07E] microbial antidiarrheals [A07F] Digestiva including enzymes [A09], antidiabetics [A10], vitamins [A11], minerals [A12], anabolic agents for systemic use [A14] and appetite stimulating agents [A15];
- agents for the treatment and prevention of diseases of the blood and blood-forming organs [B]; particularly antithrombotic agents [B01], antihemorrhagics [B02], antianaemic [B03] and other Hematologic [B06];
- agents for the treatment and prevention of diseases of the cardiovascular system [C]; in particular means for Herzherapie [C01], anti-hypertensives [C02], diuretics [C03], peripheral vasodilators [C04], vasoprotectors [C05], antihypotensives [C06A], β-adrenoceptor antagonist [C07], calcium channel blockers [C08], means with acting on the renin-angiotensin system [C09] and lipid lowering agents [C10];
- Dermatological [D]; in particular antifungals for systemic use [D01B], antipsoriatics for systemic use [D05B], anti-acne preparations for systemic use [D10B];
- agents for the treatment and prevention of diseases of the genitourinary system and sex hormones [E]; particularly gynecological antiinfectives and antiseptics [G01], pains [G02A] labor retardant sympathomimetic [G02CA], prolactin inhibitors inhibitors [G02CB], hormonal contraceptives for systemic use [G03] and Urologicals [G04];
- systemic hormone preparations exclusively sex hormones and insulins [H]; particularly pituitary and hypothalamic hormones and analogues [H01] corticosteroids for systemic use [H02], thyroid preparations [H03], pancreatic hormones [H04], and means for regulation of calcium homeostasis [H05];
- anti-infectives for systemic use [J]; particularly antibiotics for systemic use [J01], antimycotics for sytemischen use [J02], against mycobacteria [J04], anti-viral agents for systemic use [J05], immune sera and immunoglobulins [J06], and vaccines [J07]);
- antineoplastic and immunomodulating agents [L] (especially antineoplastic agents [L01], agents for endocrine therapy [L02], immunostimulants [L03] and immunosuppressive agents [L04];
- agents for the treatment and prevention of diseases of the muscles and the skeletal system [M]; especially antiinflammatories and antirheumatics [M01], peripherally acting muscle relaxants [M03A], direct-acting muscle relaxants [M03C], gout agents [M04], and agents for treating bone diseases [M05];
- agents for the treatment and prevention of diseases of the nervous system [N]; in particular salicylic acid and its derivatives [N02BA] pyrazolones [N02BB] anilides [N02BE], ergot alkaloids [N02CA] corticosteroid derivatives [N02CB], selective serotonin 5HT 1 agonist [N02CC], hydantoin derivatives [N03AB] , oxazolidine derivatives [N03AC] succinimide derivatives [N03AD] carboxamide derivatives [N03AF], fatty acid derivatives [N03AG], anti-Parkinson agents [N04]), antipsychotics [N05A], antidepressants [N06A], anti-dementia drugs [N06D], parasympathomimetics [N07A] and antivertiginous [N07C];
- antiparasitic agents, insecticides and repellents [P]; particular agents against protozoal diseases [P01], anthelmintics [P02] and agents against ectoparasites including scabicides, insecticides and repellents [P03];
- agents for the treatment and prevention of diseases of the respiratory tract [R]; in particular nasal preparations [R01], neck and throat infections [R02], means for obstructive airway diseases [R03], expectorants, excluding combinations with antitussives [R05C] and antihistamines for systemic use [R06];
- agents for the treatment and prevention of diseases of the sensory organs [S]; in particular otologicals [S02];
- general diet [V06] and radiotherapeutic agents [V10]

as used by the WHO for the classification of drugs where here too the names given in square brackets correspond to the ATC Index, (preferably, as of January 2005).

Preferably, the inventive dosage form contains a substance (A) or more substances (A) selected from the group consisting of 4-aminomethyl benzoic acid, abacavir, abamectin, abciximab, Abibendan, abrin, acamprosate, acarbose, acebutolol, aceclidine, aceclofenac, acediasulfone, acemetacin, acenocoumarol, acetazolamide, acetoacetic acid, acetyl digoxin, Acetylandromedol, acetylcysteine, β-acetyldigoxin, Acetylhistamin, acetylsalicylic acid, acetylthiocholine, acyclovir, acipimox, acitretin, aclarubicin, aconitine, Acriflavinium chloride, acrivastine, Actinoquinol, Acylaminopenicillin, adalimumab, adapalene, adefovir, adefovir dipivoxil , adenosine, adenosine phosphate, adenosine triphosphate, Adipiodon, adrenaline, aescin, agalsidase Alfa, agalsidase beta, agaric, ajmalin, alanine, albendazole, alcuronium, aldesleukin, aldosterone, alemtuzumab, alendronate, alfacalcidol, alfuzosin, Algeldrat F, alitretinoin, alizaprid, allantoin F , allopurinol, Allylisorhodanat, almasilate F, Almo triptan, α-acetyldigoxin, alprenolol, alprostadil, alteplase, aluminum glycinate F, aluminum hydroxide F, aluminum phosphate, F, aluminum triformate, amantadine, ambazone, ambroxol, Ambutonium bromide, formic acid, amikacin, Amidefrin, diatrizoic acid, amifostine, amikacin, amiloride, amino-acetic acid, aminoglutethimide, aminophylline, Aminoquinurid, amiodarone, amisulpride, amitriptyline, amitriptyline, amlodipine, amorolfine, amoxicillin, amphotericin B, ampicillin, amprenavir, amylmetacresol, amyl nitrite, anagrelide, anakinra, anastrozole, ancrod, anistreplase, antazoline, antithrombin III, apomorphine, apraclonidine, aprepitant, aprindine, aprotinin, Arcitumomab, arginine, Aripiprazole, arsenic trioxide, artemether, articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid, atazanavir, atenolol, atorvastatin, atosiban, atovaquone, atracurium, atracurium besilate, atropine, auranofin, azapropazone, azathioprine, azelaic acid, azelastine, azidothymidine, azithromycin, azlocillin, aztreonam, N2-alanyl levoglutamid, p-aminosalicylic acid,
Bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, bamethan, bamipine, barbexaclone, barium F, barnidipine, basiliximab, batroxobin, becaplermin, beclomethasone, Bedamustin, befunolol, Bemiparin, benactyzine, benazepril, bencyclane, bendazac, bendroflumethiazide, benproperine, benserazide, Benzaserid , benzathine, benzatropine, benzbromarone, benzocaine, benzoyl peroxide, Benzyclan, benzydamine, benzylpenicillin, Benzylphenylglykolat, betacarotene, betahistidine, betahistine, betamethasone, Bethanechol, betaxolol, bethanechol chloride, Betiatid, bexarotene, bezafibrate, Bibenzonium bromide, bicalutamide, Bicisate, bifonazole, bimatoprost , biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting factor VII, VIII, IX, X, XIII, Bornapin, Bomaprin, bortezomib, bosentan, botulinum toxin type B, brimonidine, brinzolamide, brivudine, bromhexine, bromocriptine, bromperidol, brompheniramine, brotizolam, budesonide , budipine, bufexamac, buflomedil, bumetanide, bunazosine, buphenin, bupivacaine, bupranolol, bupropion, Buserelin, buspirone, busulfan, butalamine, butanilicaine, Butenafine, Butetamat, Butinolin, butizide, butylscopolaminium,
5-Chlorcarvacrol, C1-inhibitor, cabergolin, cadexomer iodine, cafedrine, calcipotriol, calcitonin, calcitriol, camylofine, candesartan cilexetil, Canrenoinsäure, capecitabine, capreomycin, capsaicin, captopril, carazolol, Carbaldrat F, carbamazepine, carbasalate calcium, carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin, Carglumic Acid, Carglumic acid, carmustine, caroverine, carteolol, carvedilol, caspofungin, cefaclor, cefadroxil, cefalexin, cefaloridine, cefamandole, cefazolin, cefdinir, cefepime, Cefetametpivotil, cefixime, cefodizime, cefoperazone, cefotaxime, cefotiam , cefoxitin, cefpirome, cefpodoxime, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine, cetrimide, cetrimonium bromide, cetrorelix, cetuximab, Cetylpiridinium, chenodeoxycholic acid, quinidine, quinine, quinine-iron citrate F, quinine tannate F, chlorambucil, chloramphenicol, Chlorbutinol, chlorhexidine, chlormidazole, chlorobutanol, chloro quin, chloroxylenol, chlorpheniramine, chlorphenesin, chlorphenoxamine, chlorpromazine, Chlorprotheaxin, chlorprothixene, chlorthalidone, chlortetracycline, chlorzoxazone, choline, chondroitin, choriogonadotropin alfa, chorionic gonadotropin, Chrysarobin, chymotrypsin, cicletanine, Ciclopirox, ciclosporin, cidofovir, cilastatin, cilazapril, cimetidine, cinacalcet , cinchocaine, cinnarizine, Cinolazepam, ciprofloxacin, cisapride, cisatracurium besilate, cisplatin, citalopram, citicoline, cladribine, clarithromycin, clavulanic acid, clemastine, clenbuterol, clindamycin, clioquinol, clobetasol, clobetasone, clobutinol, clocortolone, clodronic acid, clofibrate, clomiphene, clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebol, Clostridium botulinum, clotrimazole, Cloxiquin, clozapine, cocarboxylase, colchicine, colecalciferol, colesevelam, colestipol, cholestyramine, Colfosceril palmitate, colistin, collyrium Zinci F, corticorelin, corticotrophin, cortisone, cresol, croconazole, cromolyn Crot Amiton, Cryofluoran, coumarin, Cyanamid, cyanocobalamin, cyclizine, Cyclobutyrol, cyclopentolate, cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine, cytarabine, cytarabine,
2,4-dichlorobenzyl, 2-diethylaminoethanol, dacarbazine, daclizumab, dactinomycin, dalfopristin, dalteparin, danaparoid, danazol, dantrolene, dapiprazole, dapsone, darbepoetin alfa, darifenacin, daunorubicin, Deamol, deanolace, decarbazine, dectaflur F, deferiprone, deferoxamine, delapril, demeclocycline, Denaverine, depreotide, dequalinium, desflurane, desipramine, desirudin, deslanoside, desloratadine, Desmeninol, desmopressin, desogestrel, desoximetasone, deoxyribonuclease, Detajmium, dexamethasone, dexchlorpheniramine, dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan, diacerein, diacetylmorphine, dibenzepin, dibotermin Alfa, diclofenac, diclofenamide, didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin, diflucortolone, diflunisal, digitoxin, digoxin, dihydralazine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydroergotamine, dihydroergotoxine, dihydrotachysterol, diisopropylamine, chlorazepate, diltiazem, dimenhydrinate, Dimepranol , dimercaprol, D imethylsulfoxid, dimetindene, Dinatriumselenit, dinoprost, dinoprostone, Diosmin, diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrin, diprophylline, dipyridamole, disopyramide, nitrous oxide, distigmine, disulfiram, dithranol, dixyrazine, D-norpseudoephedrine, dobesilate calcium, dobutamine, docetaxel, dofetilide, dolasetron , domperidone, donepezil, dopamine, dopexamine, dornase Alfa, dorzolamide, dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline, doxylamine, Drofenin, droperidol, drospirenone, drotrecogin alfa, Duloxetine, dutasteride, dydrogesterone, N, N'-dihydroxymethyl Urea,
Ebastine, econazole, ecothiopate iodide, efalizumab, efavirenz, eflornithine, ferric ammonium citrate F, iron oxide superparamagnetic, elcatonin, eletriptan, emedastine, emepronium, emepronium Carragenat, emetine, emtricitabine, enalapril, enalaprilat, enflurane, enfuvirtide, enoxacin, Enoxapann, entacapone, ephedrine, ephedrine Racephedrin, epinastine, epinephrine, epirubicin, epoetin alfa, epoetin beta, epoetin delta, epoprostenol, Eprazinon, eprosartan, eptacog Alfa, eptifibatide, eptotermin Alfa, erdosteine, ergocalciferol, ergonovine, Ergotamid, ertapenem, erythromycin, escitalopram, esmolol, esomeprazole, estradiol, estramustine, estriol, estrone, ethacrynic acid, etamivan, etanercept, ethacridine, ethambutol, ethaverine, ethinyl estradiol, ethisterone, ethosuximide, etidronic acid, etilefrine, etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel, etoposide, etoricoxib, Exametazim, exemestane, ezetimibe,
3-fluorotyrosine, famciclovir, famotidine, felbamate, felbinac, felodipine, fenbufen, fendiline, fenofibrate, fenoterol, fenticonazole, fexofenadine, fibrinogen, fibrinolysin, filgrastim, finasteride, flavoxate, flecainide, flucloxacillin, fluconazole, fludarabine, fludeoxyglucose ^[18 F] fludrocortisone, flufenamic, flumazenil, Flumetason, flunarizine, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluphenazine, fluorescein dilaurate, fluorescein sodium, fluorometholone, fluorouracil, fluorine phosphoric acid, fluorosilane, Fluoxetil, fluoxetine, flupentixol, fluphenazine, flupirtine, fluprednidene, flurbiprofen, flutamide, fluticasone, flutrimazole, fluvastatin, fluvoxamine, folinic acid, follitropin alpha, follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux, formestane, formoterol, fosamprenavir, foscarnet, fosfestrol, fosfomycin, fosinopril, fosphenytoin, fotemustine, framycetin, framycetin, frovatriptan, fulvestrant, furosemide, fusafungine, fusidic acid, phytic acid,
Gabapentin, gadobenate, Gadobutrol, gadodiamide, gadopentetic acid, gadoteridol, gadoteric acid, galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin, gemcitabine, gemfibrozil, gentamicin, Gepefrin, gestodene, glatiramer, glibenclamide, Glibomurid, gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glucagon, glutamine, glutamic acid, glycopyrronium, glycopyrronium bromide, glycyrrhetinic acid, gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin, griseofulvin, ouabain, guaiacol, guanethidine, guanfacine,
¹³ C-urea, 4-hydroxybutyric acid, halcinonide, halofantrine, halometasone, Halopetidol, halothane, heme, hematoporphyrin, heparin, Hepatitis B Vaccine, heptaminol, hexobarbital, hexobendine, hexoprenaline, histamine, histidine, homatropine, homofenazine, human albumin, hyaluronidase, hydralazine , hydrastinine, hydroquinone, hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin, hydroxycarbamide, hydroxychloroquine, hydroxycine, hydroxylamine, hydroxyprogesterone, hydroxyzine, hymecromone,
Ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide, idarubicin, ifosfamide, iloprost, imatinib, imatinib Mesilate, imidapril, imiglucerase, imipenem, imipramine, imiquimod, Immunocyanin, Indanazoline, indapamide, indinavir, indium chloride ^[111 In], indobufen, indometacin , indoramin, infliximab, inosine, insulin, insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, interferon alfa, interferon alfa-2b, interferon alfacon-1, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, Iobitridol, iodine, iodamide, iodixanol, ioflupane ^[123 I], iohexol, iomeprol, iopamidol, iopentol, iopromide, iosarcol, iotrolan, iotroxic acid, ioversol, ioxaglic acid, Ioxitalaminsäure, Ipatropium, irbesartan, irinotecan, irinotecan, isepamicin, Isoaminil , isoconazole, isoflurane, isoleucine, isoniazid, isonicotinic, isoprenaline, isosorbide, Isospagluminsäure, isotretinoin, isoxsuprine, isradipine, itraconazole,
josamycin,
Potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone, ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen, collagenase, creosote,
Labetalol, lacidipine, lactitol, lamivudine, Lamottigin, lanreotide, lansoprazole, laronidase, latanoprost, leflunomide, lenograstim, lepirudin, lercanidipine, letrozole, leucine, leuprorelin, levallorphan, levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine, levocetirizine, levodopa, levofloxacin, Levofolinat calcium, levomepromazine, levomethadyl, levonorgestrel, Levopropylhexedrin, levosimendan, levothyroxine, lidocaine, lincomycin, lindane, linezolid, liothyronine, lisinopril, lisuride, lobeline, lodoxamide, lofepramine, lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine, lorazepam oxide, lornoxicam, losartan, lovastatin, lumefantrine, lutropin alfa, lymecycline, lynestrenol, lypressin, lysine,
Magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir, manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate, Mecloxamin, meclozine, medrogestone, medroxyprogesterone, mefenamic acid, mefloquine, megestrol, melitracen, Melperol, melperone, melphalan, memantine, menadione, mepacrine, mepartricin, mephenytoin, mepindolol, mepivacaine, mepyramine, Mequinol, Mercaptamin, mercaptopurine, meropenem, mesalazine, mesna, mesterolone, mesuximide, metaclazepam, dipyrone, methamphetamine, methenolone, Metenolonacetat, metformin, Methanthelinium, methazolamide, methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen, 8-methoxypsoralen, methyl 5-aminolevulinate, Methylbenactyzium bromide, methyldopa, methylergonovine, methylprednisolone, Methylrosanilinium, methyltestosterone, Methylthionium chloride, methysergide, metildigoxin, metipranolol, metoclopramide, metoprolol, Metrixen, metronidazole, mexiletine, mezlocillin, mianserin , miconazole, midodrine, mifepristone, miglitol, miglustat, milnacipran , Milrinone, miltefosine, minocycline, minoxidil, mirtazapine, misoprostol, mitobronitol, mitomycin, mitotane, mitoxantrone, mivacurium chloride, mivacuronium, mizolastine, moclobemide, moexipril, molgramostim, molsidomine, mometasone, monochloroacetic acid, montelukast, Moroctocog Alfa, moxaverin, moxifloxacin, moxonidine , mupirocin, mycophenolate mofetil,
Nadifloxacin, Nadrolondecanonat, nadroparin calcium, naftidrofuryl, naftifine, nalbuphine, nalide, nalmefene, nalmexone, naloxone, naltrexone, naluphine, naphazoline, 2- naphthol, naproxen, naratriptan, naratriptan, nateglinide, sodium aurothiomalate, sodium phenylbutyrate, sodium fluoride, sodium hyaluronate, sodium iodide ^[131l I], sodium ^[99 Mo], sodium phenylbutyrate, N-butyl-p-aminobenzoate, N-narcotic analgesics, nebivolol, nedocromil, nefazodone, nefopam, nelfinavir, neomycin, neostigmine, neostigmine Metilsulfat, netilmicin, nevirapine, N-heptyl 2-phenylglycinate, nicardipine, nicergoline, nicethamide, Niclosamin, Nicoboxil, nicorandil, nicotine, nicotinaldehyde, nicotinamide, Nicotinresinat, nicotinic acid, nicotinic acid, nicotinyl alcohol, nifedipine, niflumic acid, nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, Nimustatin, nisoldipine, nitrendipine, Nitric oxides, nitrofurantoin, nitroglycerine, nizatidine, N-methylephedrine, nonacog Alfa, nonivamide, noradrenaline, Norelgestromi n, norepinephrine, norethisterone, norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline, noscapine, nystatin,
Obidoxime chloride, Octafluoropropane, Octocog Alfa, Octodrin, octreotide, odansetron, ofloxacin, Olaflur F, olanzapine, olmesartan medoxomil, olopatadine, olsalazine, omeprazole, omoconazole, ondansetron, opipramol, Oral Cholera Vaccine, Orciprenalin, orlistat, Omipressin, orphenadrine, oseltamivir, osteogenic protein-1: Bmp-7, oxaprozin, oxatomide, oxcarbazepine, Oxedrintartrat, Oxetacain, oxiconazole, oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid, 2-oxo-3-methyl valeric acid, 2-oxo-3-phenylpropionic acid, 2 -oxo-4-methyl valeric acid, Oxprenofol, oxybuprocaine, oxybuprocaine, oxybutynin, oxybutynin, oxyfedrine, oxymetazoline, oxytetracycline, oxytocin,
Paclitaxel, Palinavir, palivizumab, pamidronate Pancurmium, pantoprazole, papaverine, paracetamol, paraldehyde, parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon alfa, pegvisomant, pemetrexed, penbutolol, penciclovir, penfluridol, penicillamine, Penperidol; Pentaerythrityl tetranitrate, pentamidine, Pentetrazol, Inpentetreotide, pentosan polysulphate sodium, pentoxifylline, Pentoxyverine, perazine, perchloric acid, Perflenapent, Perflisopent, perflutren, pergolide, perindopril, perphenazine, phenacetin, Phenamazid, phenazone, Phenazopyridine, pheniramine, phenol, phenolphthalein, phenoxybenzamine, phenoxymethylpenicillin , phenprocoumon, phentolamine, phenylalanine, phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucinol, pholedrine, phthalylsulfathiazole, physostigmine, phytomenadione, phytosterol, picric acid, pilocarpine, pimecrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone, pipamperone, Pipazetat, pipecuronium bromide , pipemidic acid, Pipenzolat, piperacillin, Piprinhydrinat, piracetam, pirarubicin, pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam, pizotifen, podophyllotoxin, polidocanol, polycarbophil, Polyestradiol phosphate, polymyxin B, polymyxin B, polystyrenesulfonic acid, porfimer, Prajmalin, Prajmal ium bitartrate, pramipexole, pranoprofen, prasterone, pravastatin, prazepam, prazosin, prednicarbate, prednisolone, prednisone, pregabalin, preglumetacin, pridinol, prilocaine, primaquine, primidone, Prithipendyl, procaine, procainamide, Procarbazil, procarbazine, procyclidine, progesterone, proglumetacin, proglumide , proguanil, proline, promethazine, propacetamol, propafenone, propranolol, propicillin, propiverine, propofol, propranolol, propylthiouracil, propyphenazone, protamine, protamine sulfate, protein C, prothipendyl, prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline, pseudoephedrine, pulmonary, pyrantel, pyrazinamide, pyridostigmine, pyridostigmine bromide, pyridoxine, 3-pyridylmethanol, pyrimethamine, zinc pyrithione, pyritinol, pyrogallol, pyrvinium, pyrvinium embonate,
Quecksilberamidochlorid, quetiapine, quinagolide, quinapril, quinupristin,
Rabeprazole, Racephedrin, raloxifene, raltitrexed, ramipril, ranitidine, rasburicase, raubasine, reboxetine, repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol, Reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin, rifaximin, rilmenidine, riluzole, rimexolone, risedronic acid, risperidone, ritonavir, rituximab, rivastigmine, rizatriptan, rocuronium bromide, rofecoxib, ropinirole, ropivacaine, ropivacaine, rosiglitazone, red mercury sulfide F, roxatidine, roxithromycin,
Salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid, Salverin, samarium ^[153 Sm] lexidronam, saquinavir, sulfur hexafluoride, scopolamine, selegiline, Selensulfld, serine, Sermorelin, sertaconazole, sertindole, sertraline, sevelamer, sevoflurane, sibutramine, silver chloride F, sildenafil , silibinin, simvastatin, sirolimus, Solutio Formaldehydi, somatostatin, somatropin, sotalol, Spagluminsäure, sparteine, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptodornase, streptokinase, streptomycin, strontium ranelate, strontium chloride, strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethoxazole, Sulfamethoxydiazin, sulfametrole, sulfanilamide, sulfasalazine, sulfathiazole, sulfisomidine, sulindac, sulodexide, Sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sulthiame, sumatriptan, suxamethonium,
Tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin, taurolidine, tazarotene, tazobactam, tegafur, teicoplanin, telithromycin, telmisartan, temoporfin, temozolomide, tenecteplase, teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, teriparatide , terizidone, terlipressin, testosterone, testosterone propionate, Testosteronundecanonat, tetracaine, tetracosactide, tetracycline, tetrafluoroborate-1 +, tetrofosmin, tetryzoline, thallium chloride ^[201 TI], theobromine, Theodrenalin, Theodrenalin, theophylline, thiamazole, thiamine, thiethylperazine, thiocolchicoside, thiopental , Thiondazin, thiotepa, threonine, thrombin, thrombokinase, thymol, thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone, ticlopidine, tiludronic acid, timolol, tinzaparin, tioconazole, thioguanine, tiotropium bromide, tirilazad, tirofiban, Tisopurin, Tizamidin, tizanidine, tobramycin , tocainide, Tolazolin, tolbutamide, tolcapone, tolfenamic acid, tolmetin, tolperisone, tolterodine, Topiramate, topotecan, torasemide, toremifene, tramazoline, trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, tretinoin, triamcinolone, triamcinolone acetonide, triamterene, trichloroacetic acid, triethylperazine, trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine, trimecaine, trimegestone, trimetazidine, trimethoprim, trimipramine, tripelennamine, triprolidine, triptorelin, Tritoqualin, trofosfamide, tromantadine, trometamol, tropicamide, tropisetron, trospium, tryptophan, tubocurarine chloride, tulobuterol, tyloxapol, tyrosine, tyrothricin,
Unoprostone, uRapid, urapidil, urokinase, ursodeoxycholic acid,
Valaciclovir, valdecoxib, valganciclovir, valine, valproic acid, valsartan, vancomycin, vardenafil, Vecurmium, vecuronium bromide, venlafaxine, verapamil, verteporfin, vigabatrin, Viloxacin, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, Viquidil, voriconazole, votumumab,
hydrogen peroxide,
Xantinol nicotinate, Xipamide, xylometazoline,
Yohimbine, yttrium ⁹⁰ Y chloride,
Zalcitabine, zaleplon, zanamivir, zidovudine, Zinc Acetate Dihydrate, zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zopiclone, zotepine, Zucklopantexol, and zuclopenthixol.

The above compounds are primarily by their international ioneln name (INN) named and known in the art. For further details, for example, can be made to International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organization (WHO).

Further, in addition to achieve the necessary breaking strength of the dosage form according to the invention at least one natural, semi-synthetic or synthetic wax (D) can be used (= component (D)). Preferably waxes having a softening point of at least 50 ° C, more preferably at least 55 ° C, more preferably at least 60 ° C, most preferably at least 65 ° C and especially at least 70 ° C. Particularly preferred are carnauba wax and beeswax. Most particularly preferred is carnauba wax. Carnauba wax is obtained from the leaves of the Camaubapalme and has a softening point of at least 80 ° C a natural wax. When additional use of this wax component together with at least one polymer (C) is used in quantities such that the dosage form exhibits a breaking strength of at least 400 N, preferably at least 500 N,.

As auxiliary substances (B) which are customary for the formulation of solid dosage forms known adjuvants can be used. These are preferably plasticisers, such as triacetin and polyethylene glycol, preferably a low molecular weight polyethylene glycol, auxiliary substances which influence active ingredient release, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, very particularly preferably hydroxypropyl methylcellulose, and / or antioxidants. Preferably cellulose ethers, Celluloseester and / or acrylic resins are used as hydrophilic matrix materials are polymers, especially preferably used. are very particularly preferred as matrix materials ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or their derivatives such as their salts, amides or esters. Suitable antioxidants are ascorbic acid are suitable, butylhydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and α-tocopherol.

The antioxidant is preferably used in amounts of 0.01 to 10.%, Preferably 0.03 to 5 wt.%, Based on the total weight of the dosage form.

The preparations according to the invention are distinguished in that they can not be pulverized due to their breaking strength using conventional crushing means such as a mortar and pestle. An overdose is practically impossible. However, to increase the breaking strength of the dosage form further dosage forms of the invention as auxiliaries (B) may contain further breaking strength enhancing agents.

The dosage form according to the invention is preferably solid and is suitable for oral, vaginal or rectal, preferably for oral administration. it is not film form preferably. In a further preferred embodiment the dosage form according to the invention is in the form of a tablet, a capsule or in the form of an oral osmotic therapeutic system (OROS). In a preferred embodiment the dosage form according to the invention is present as a tablet. The dosage form according to the invention may assume multiparticulate form, preferably, optionally filled or in the form of microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets in capsules, compressed into tablets, preferably for oral administration, are present. Preferably, the multiparticulates have a size or size distribution in the range of 0.1 to 3 mm, particularly preferably in the range of 0.5 to 2 mm. Depending on the desired dosage form, conventional auxiliary substances (B) are optionally also used for the formulation of the dosage form.

The dosage form according to the invention can be prepared by different methods, which are explained in more detail below:
The process for preparing the dosage form according to the invention preferably comprises the steps of:

(A) mixing the component (A), optionally (B), (C), optionally (D);
(B) optionally preforms from step (a) obtained mixture, preferably is insufficient under heat and / or force to the obtained from (a) mixture, the amount of heat supplied preferably to the component (C) to its softening point to heat;
(C) curing the mixture under heat and force, wherein the heat supply can be done during and / or prior to the application of force and is sufficient, the amount of heat applied, the component (C) to heat at least to its softening point;
(D) optionally separating the hardened mixture;
(E) optionally forms of the dosage form; and
(F) optionally coating with a film coating.

The heat can be supplied directly or with the help of ultrasound. The force and / or the shapes of the dosage form can, for example by direct or by means of extruders.

The following process variants are particularly preferred:

Process variant 1:

In this embodiment, the dosage form according to the invention is preferably produced without using an extruder, preferably by the components (A), optionally (B), (C) and the optionally present component (D) are mixed and the resulting mixture if necessary after a granulation is formed into the dosage form with preceding or simultaneous exposure to heat by force.

This heating and force for the production of the dosage form is done without using an extruder.

The mixture of components (A), optionally (B), (C) and optionally (D) takes place in a mixer known to the expert. The mixer can be for example a roll mixer, shaking, shear mixer or compulsory mixer.

The resulting mixture is preferably molded directly to the inventive dosage form with preceding or simultaneous exposure to heat by force. For example, the mixture may be formed by direct compression into tablets. In direct the simultaneous action of heat by means of the tabletting tool, ie the bottom punch, top punch and the die, the mixture to be compressed at least to the softening point of the polymer component (C) is heated and pressed thereby. In direct preceding exposure to heat to be compressed material is immediately before the tableting least up to the softening temperature of the component attempts (C) is heated and then pressed by means of the tabletting tool.

The resulting mixture of components (A), optionally (B), (C) and optionally the component (D) can also first be granulated and then molded with preceding or simultaneous exposure to heat under force to the inventive dosage form.

In each application of force, this is carried out until the dosage form has reached a breaking hardness of at least 400 N, preferably at least 500 N,.

Granulation may be performed by wet granulation or melt in known granulators.

Each of the mentioned process steps, in particular the heating steps and simultaneous or subsequent application of force for the preparation of the dosage form according to the invention is carried out without using an extruder.

Process variant 2:

In this process variant, the inventive dosage form is manufactured by thermoforming with the aid of an extruder, without causing discoloration of the extrudate is observed.

To investigate the extent of discoloration due to this thermoforming, first the color of the mixture of the starting components that make up the dosage form, without the addition of a coloring component such. B. found a coloring pigment or an intrinsically colored component (for. Example, α-tocopherol). This composition is then thermoformed according to the invention, wherein all process steps, including cooling of the extrudate, are performed under an inert gas atmosphere. In comparison, the same composition by the same method, but without an inert gas atmosphere. Of the starting composition and the dosage form according to the invention the dosage form prepared for comparison the color is determined. The determination is made by means of "Munsell Book of Color" Munsell Color Company Baltimore, Maryland, USA, 1966 edition If the color of the invention thermoformed dosage form has a color with the identification no. N 9.5 / maximum of staining with having the identification number. 5Y 9/1, thermoforming is classed as being "without discoloration". If the dosage form has a color with identification no. 5Y 9/2 or greater, as determined according to the Munsell Book of Color, the thermoforming is classed as a "with discoloration".

Surprisingly, dosage forms of the invention have not be classified according to the above classification discoloration, if the entire manufacturing process is carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere using an extruder for thermoforming.

This variant of the invention for the preparation of the dosage forms according to the invention is characterized in that one

z) components (A), optionally (B), (C) and the optionally present component (D) are mixed,
y) the resultant mixture in the extruder at least up to the softening point of component heated (C) and extruded under force through the outlet opening of the extruder,
x) forms the still plastic extrudate is singulated and dosage form
f) shaping the cooled and optionally reheated singulated extrudate into the dosage form,

wherein process steps y) and x) and optionally process steps z) and w) under an inert atmosphere, preferably nitrogen atmosphere, are carried out.

The mixing of the components according to process step z) may also proceed in the extruder.

The mixture of components (A), optionally (B), (C) and optionally (D) may also take place in a well-known to those skilled mixer. The mixer can be for example a roll mixer, shaking, shear mixer or compulsory mixer.

Preferably prior to the mixing with the other components, the component (C) and the optionally present component (D) according to the invention provided with an antioxidant. This may be by mixing the two components (C) and carried to the antioxidant, preferably by the antioxidant dissolved or suspended in a volatile solvent, and this solution or suspension with component (C) and the optionally present component (D) were homogeneously mixed, and the solvent is removed by drying, preferably under inert gas atmosphere.

The heated in the extruder at least up to the softening point of component (C), preferably molten mixture from the extruder is extruded through a die with at least one bore.

Preferably be used for implementing the method according to the invention conventional extruders, particularly preferably screw extruders which are equipped both with one or two screws.

Preferably, the extruder has at least two temperature zones, which takes place in the first zone, which is adjacent to a feed and mixing zone, if necessary, heating the mixture to at least the softening point of component (C). The throughput of the mixture is preferably from 2.0 kg to 8.0 kg / hour.

After heating to at least the softening point of component (C), the molten mixture is conveyed with the aid of the screws, further homogenised, compressed or compacted such that, immediately before emerging from the extruder die a minimum pressure of 5 bar, preferably at least 10 bar comprising , and extruded through the die as an extruded strand or strands, depending on how many holes having the nozzle. The die geometry or the geometry of the bores is freely selectable. Thus, the die or the bores may have a round, oblong or oval cross section, wherein the round cross-section preferably has a diameter of 0.1 mm to 15 mm and the oblong cross-section preferably has a maximum lengthwise extension of 21 mm and a crosswise extension of 10 mm is present. Preferably, the die or the bores have a round cross section. The jacket of the invention used according to the extruder can be heated or cooled. The corresponding temperature control, ie heating or cooling, is so arranged, comprises that the mixture to be extruded at least an average temperature (product temperature) corresponding to the softening point of component (C) and does not rise above a temperature at which the physiologically active for processing the substance (A can take) damage. Preferably, the temperature of the mixture to be extruded below 180 ° C, preferably (C) is set below 150 ° C, but at least to the softening temperature of the component.

After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands comminution of the extrudate preferably takes place. This comminution can be preferably carried out by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the aid of laser cutters.

For intermediate storage and disposal of possibly occasional extrudate or the final shape of the dosage form, no inert gas atmosphere is necessary.

The singulated extrudate may be pelletized by conventional methods or pressed into tablets to give the dosage form the final shape. However, it is also possible not to singulate the extruded strands and, with the assistance of contrarotating calender rolls comprising in their outer shell opposed indentations, into the final form, preferably, to be formed into a tablet, and to singulate these by conventional methods.

Should this not be immediately formed into the final shape, but cooled for storing optionally singulated extrudate, then after storage for an inert gas, preferably to provide a nitrogen atmosphere, which are observed during a heating of the stored extrudate up to the plasticizing and final shaping to the dosage form got to.

The force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry and the dimensioning of the exit opening so that preferably builds up in the extruder before the direct extrusion of the plasticized mixture of the requisite pressure. By simple preliminary tests the necessary extrusion parameters can be determined for each composition, which result in a dosage form with a breaking strength of at least 400 N, preferably at least 500 N.

Process variant 3:

In this process variant for the preparation of the dosage form according to the invention a homogeneous mixture of at least the component (A) and the component (C) (= binder) is first prepared. This mixture may also contain other additives such as fillers, plasticizers, lubricants or dyes are added. Preferably, a low molecular weight polyethylene glycol is used as a plasticizer.

The mixing can be carried out using conventional mixers. For example, mixers are roll mixers, which are also known as tumbler, drum or rotary mixers, container mixers, barrel mixers (drum hoop mixers or tumbling mixers) or shaking mixers, shear mixers, compulsory mixers, plow blade mixers, planetary kneader, Z kneaders, sigma kneaders, fluid mixers or intensive mixer suitable.

The selection of the suitable mixer depends among other things on the viscosity and cohesiveness of the mix.

The mixture is then subjected to shaping. Preferably during or after the ultrasonic action, the shaping of the mixture takes place, preferably by compaction.

In the ultrasonic action, it is particularly preferred that a direct contact between the mixture and the sonotrode of the ultrasound device is present. Preferably according to the inventive method, an ultrasonic device is used as shown in 1 is shown.

In this 1 means ( 1 ) The press with which the necessary force is applied, ( 2 ) The converter ( 3 ) The booster, ( 4 ) The sonotrode, ( 5 ), The die for molding ( 6 ) The bottom punch, ( 7 ) The base plate ( 8th ) and ( 9 ) The ultrasound generator and the control of the device. The reference numerals used relate solely to 1 ,

In the ultrasonic action, a frequency of 1 kHz to 2 MHz should preferably be 15 to 40 kHz are respected. The duration of the ultrasonic action should be performed until softening of the polymer (C) is achieved. Preferably, this is within a few seconds, particularly preferably within 0.1 to 5 seconds, preferably reaches 0.5 to 3 seconds.

By ultrasonic action and the force ensure uniform energy transfer, whereby a rapid and homogeneous sintering of the mixture takes place is achieved. This dosage forms are obtained which have a breaking strength of at least 400 N, preferably at least 500 N and thus are not to pulverization.

Before shaping is performed, a granulation can be carried out of the mixture, after which the resulting granules are molded under the action of ultrasound and force to the dosage form such as tablets after the mixing process.

The granulation can be carried out in known in the art machinery and equipment.

Provided that the granulation is carried out as wet granulation, granulation can be used as water or aqueous solutions, such as ethanol / water or isopropanol / water, may be used.

The mixture or the granules produced therefrom may also be subjected to further shaping a melt-extrusion, wherein the mixture is caused to melt under the action of ultrasound and force and is then extruded through nozzles. The thus obtained strands or strand obtained in this way can be isolated with the aid of known devices to the desired length. The thus isolated moldings can be processed with ultrasonication and application of force to the final form further optionally.

The final shaping to the dosage form preferably takes place under application of force in appropriate molds.

The blanks described above can also be prepared according to a calendering process by passing the mixture or the granules produced therefrom by means of ultrasonic and plasticized first force and be extruded through a corresponding nozzle. These extrudates are then shaped between two counter-rotating molding rolls to the final form, preferably under force.

As already mentioned, shaping to yield the final shape of the dosage form by use of a mixture comprising the substance (A) and the polymer (C) having a breaking strength of at least 400 N, preferably at least 500 N, preferably in powder form by direct compression with application of force wherein, prior to this mixing or during the force effect of ultrasound is provided. The force is a maximum of the force that is commonly used for shaping of dosage forms such as tablets or granules for pressing to the corresponding final shape.

The tablets according to the invention may also be multilayer tablets.

In multilayer tablets, at least the layer containing the substance (A), an ultrasonic action, and the action of force is to be subjected.

The corresponding necessary application of force may be applied to the mixture with the aid of extruder rolls or calender rolls. Preferably, the shape of the dosage forms by direct compression of a powdered mixture of the components of the dosage form or corresponding granules formed therefrom, whereby preferably during or before shaping the ultrasonic action takes place. This action continues until the polymer is softened (C), which is typically achieved in less than 1 second to at most 5 seconds.

Process variant 4:

In this process variant for the preparation of the dosage form according to the invention, the components (A), (C) and optionally (D) and optionally present auxiliary substances (B), such as antioxidants, plasticizers and / or delayed-release auxiliary substances with the help of a planetary roller extruder, to the inventive dosage form processed.

Planetary roller extruders are known and are, inter alia, in detail in the Handbook of Plastics Extrusion Technology 1 (1989) "Foundations" in section 1.2 "Classification of extruders" pages 4 to. 6 The corresponding description is hereby introduced as a reference and is deemed part of the disclosure.

In the following, the use of a planetary roller extruder in the inventive method is based on the 2 and 3 explained. These explanations are merely exemplary and do not restrict the general inventive idea.

2 shows the section of a planetary roller extruder and

3 shows the operation of the planetary roller extruder.

In 2 a planetary roller extruder is shown, which can be used according to the invention. This extruder essentially comprises a shaft 1 , which with respect to the transport direction of the mixture to be extruded of the components listed above first as auger 5 and subsequently as the central spindle 3 of the planetary roller extruder is designed. Around the central spindle 3 preferably three to seven planetary spindles 4 arranged, in turn, by a casing in the form of a housing 6 are surrounded.

In the planetary roller extruder is described with reference to 2 the extrusion of the next process of the invention for use composition for the preparation of a pharmaceutical dosage form, preferably carried out as follows. As indicated by arrow 2 shown, the components are to be extruded through the dispensing unit 7 in the region of the auger 5 and metered (not shown drive) by rotating in the direction of the central spindle 3 promoted. The skilled artisan understands that in the region of the auger mixing of the starting materials (components) is possible. but it is also possible to pre-mix the components of the dosage form and this mixture via the metering unit 7 in the region of the auger 5 to dose. In the catchment area of the planetary-gear extruder, the mixture is promoted. By heating to at least the softening point of component (C) is melted and the mixture there in the region of the central spindle, that is, in the extrusion area, the molten mixture by cooperation of the central spindle 3 and the planetary spindles 4 promoted further homogenised, compressed or compacted and through the nozzle 8th as extruded strand or strands, depending on how many holes having the nozzle, extruded. The die geometry or the geometry of the bores is freely selectable. Thus, the die or the bores may have a round, oblong or oval cross section, wherein the round cross-section preferably having a diameter from 0.1 mm to 15 mm and the oblong cross-section is preferably present with a maximum longitudinal extension of 21 mm and a crosswise extension of 10 mm , The extrusion die may also be designed as a slot. Preferably, the die or the bores have a round, oval or oblong cross-section. Both the jacket 6 of the invention employed in accordance with planetary-gear extruder and the central spindle can be heated or cooled. The corresponding temperature control, ie heating or cooling, depends on that the mixture to be extruded comprises at least an average temperature corresponding to the softening point of component (C) and does not rise above a temperature at which the to be processed substance (A) may be damaged. Preferably, the temperature of the mixture to be extruded below 180 ° C, preferably (C) is set below 150 ° C, but at least to the softening temperature of the component. The reference numerals used relate solely to 2 and 3 ,

After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands is effected in a non- 2 Crushing the extrudates shown. This comminution can be preferably carried out by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the aid of laser cutters.

If necessary, after further cooling of the crushed extrudates, which are preferably present in slices, is optionally carried out a forming into the final shape of the dosage form, wherein, if necessary, again the influence of heat takes place.

This shaping into tablets, for example may take place in that the plastic extrudate by means of two counter-rotating rolls having preferably for plasticizing opposed recesses in the roller shell, the execution of which determines the form of tablets, is molded under compression.

It is also possible to form from the singulated extrudates tablet each by means of an optionally heated mold and at least one forming punch. For this, the obtained after the crushing of the extruded strand cylindrical granules can be preferably used. Except compressed into tablets, these granules obtained or other multiparticulate forms such as pellets or spheroids, can also be filled into capsules to be used as a dosage form manufactured according to the invention.

In a further preferred embodiment, the extruded through a plurality of holes in the extrusion lines can be merged according to a rope production, in comparison with the individual extruded strands thicker strand optionally after cooling thereof by braiding or wrapping around. This strand may optionally be further processed in accordance with the above-mentioned crushing and deformation of a single strand by dissolving with a suitable solvent or by heating to the softening point of the polymer (C) and optionally removing the solvent.

3 shows a cross section through the planetary roller extruder. To the rotating central spindle 3 are at least three, in the case shown, 6 , Planetary spindles 4 arranged, the flanks 41 a with the edges 31 the central spindle 4 and on the other with the edges 61 of the shell 6 interaction of the planetary roller extruder. By the rotation of the central spindle 3 and the unrolling of the respective edges to each other to rotate the planetary spindles 4 each as with arrow 42 around its own axis and how Arrow 43 clarified to the central spindle 4 around. Characterized according to the invention desired compression or compaction of the invention used according to component mixture of the dosage forms according to the invention is effected. The reference numerals used relate solely to 2 and 3 ,

If necessary, the upcoming used planetary roller extruder may have not only an extrusion area, but also at least one further, to optionally degas the mixture to be extruded.

The inventive method can be carried out batchwise or continuously, preferably continuously carried out.

Process variant 5:

To carry out this variant for the preparation of the dosage form according to the invention, the components (A), (C) and optionally (D) and optionally present auxiliary substances (B), such as antioxidants, plasticizers and / or delayed-release auxiliary substances, with the addition of a solvent for which are at least component (C), that is processed for the polymer or polymers (C) to the dosage form.

For this purpose, the components are mixed (A), optionally (B), (C) and the optionally present component (D) and molded, the resulting formulation mixture after the addition of the solvent and optionally after granulation to the dosage form.

The addition of the solvent for the polymer (C) is effected at least in amounts such that the formulation mixture is moistened evenly.

As a solvent for the polymer (C) is preferably an aqueous solvent such as water, mixtures of water and aliphatic alcohols, preferably alcohols with C1 to C6, esters, ethers, hydrocarbons are suitable, more preferably distilled water, short chain alcohols, such as methanol, ethanol, isopropanol, butanol or aqueous alcohol solutions.

The addition of the solvent is preferably carried out with stirring. Subsequently, the uniformly moistened mass is dried. The drying preferably takes place under the action of heat at temperatures at which discoloration of the composition can be excluded. By simple preliminary this temperature is detected.

Before or after drying, the mass may be divided into partial masses, which preferably correspond to the mass of a unit of the dosage form. The appropriately dried materials are then formed into the dosage form.

This is preferably done using tablet presses.

It is also possible to perform the moistening of the formulation mixture, that the formulation mixture, preferably distributed before the addition of the solvent in forms part compositions to be dispersed in a liquid dispersant with stirring and then add the solvent. The component (C) is not soluble in the dispersant, which must be miscible with the solvent.

As dispersing agents are preferably hydrophilic solvents such as aliphatic alcohols, ketones, esters are suitable. Short-chain alcohols are preferably used.

Alternatively, the humidification of the formulation mixture may also be effected so that the solvent is incorporated as the foam in the formulation mixture. Preferably, such foam of the solvent with the help of high-speed mixer, preferably prepared by addition of conventional foam stabilizers. For example, suitable as stabilizers, hydrophilic polymers such as hydroxypropylmethylcellulose.

Preferably, the foam preferably with stirring thereby obtain a granulated mass is incorporated into the formulation mixture.

The granulated mass is dried before or after division into sub-compositions which preferably corresponds to the mass of a unit of the dosage form and then shaped into the dosage form.

The drying and shaping can preferably be carried out as stated above. The inventive method can also be carried out so that as much solvent is added to the formulation mixture to a moldable paste.

Such a paste may be performed before or after drying, which as noted above, be divided into partial masses and the dried compositions are optionally shaped according to a further distribution in each case on a mass corresponding to the mass of a unit of the dosage form to dosage form or reshaped.

It is possible to form the partial masses in the form of strands which can be generated by means of a sieve or a Strangformers. The dried strands are preferably singulated and formed into the dosage form. This molding is preferably performed with the aid of a tablet press using forming rolls or rolls equipped shaped strips.

It is also possible to process the paste into a sheet-like structure and to punch the dosage form from the dried structure.

Advantageously, the paste is processed by means of an extruder, said strands or sheet-like structures are produced, depending on the design of the extrusion, which are singulated by chopping or cutting or punching. The separated part mass can be molded, formed or punched into the dosage form as stated above. Corresponding devices are known in the art.

In this case, the inventive method can be performed continuously or batchwise.

It is also possible to add so much solvent to the formulation mixture, that at least the polymer component is dissolved (C). Such a solution or dispersion / suspension is preferably processed into a sheet-like structure, wherein preferably an extruder with a flat die is used, or the solution is poured out onto a sheet-like, flat surface.

After drying, as indicated above, the dosage forms may be obtained by stamping or calendering of the sheet-like structures. It is also possible to process the solution as indicated above to form extrudates and these, preferably after drying to separate, and to form the dosage form.

Alternatively, the solution can also be divided into subsets such that, after drying them respectively corresponds to the mass of a unit of the dosage form, said forms already be used according to the shape of a unit of the dosage form, preferably for it.

Provided that the solution is divided into arbitrary subsets, the subsets can be optionally recombined after drying and formed into the dosage form, such as. For example, be filled into a capsule or compressed into a tablet.

Preferably, the offset with solvent mixtures formulation are processed at temperatures of 20 ° C to 40 ° C, except for the drying to remove the solvent and the dispersant may be present no higher temperature can be employed. The temperature for drying must be selected below the decomposition temperature of the components. Optionally, a drying according to the above-described drying can be carried out again after the shaping to the dosage form.

There are also combinations of individual steps of the above process variants are possible to produce the dosage form.

The inventive dosage form comprises a controlled release of the active ingredient. It is preferably suitable for a 2x daily administration to patients.

The dosage form according to the invention may comprise one or more substances (A) at least partially in a moreover retarded form, wherein the retardation with the aid of customary processes known to the person skilled in materials and methods can be achieved, for example by embedding the substance in a delayed-release matrix or by applying one or more delayed-release coatings. but the substance release must be controlled so that by the addition of retarding materials are not impair the necessary hardness.

The controlled release from the dosage form according to the invention is preferably achieved by embedding the substance in a matrix. The serving as matrix materials control the release excipients. Matrix materials may, for example, be hydrophilic, gel-forming materials, from which release proceeds mainly by diffusion, or hydrophobic materials, from which release proceeds mainly by diffusion from the pores in the matrix.

Matrix materials physiologically acceptable, hydrophobic materials can be used, which are known in the art. Preferably cellulose ethers, Celluloseester and / or acrylic resins are used as hydrophilic matrix materials are polymers, especially preferably used. are very particularly preferred as matrix materials ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or their derivatives such as their salts, amides or esters.

Also preferred are matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof. Particularly preferred hydrophobic materials mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof.

It is also possible to use mixtures of the above hydrophilic and hydrophobic material is as matrix materials.

Further, the components (C) and optionally present component (D), which serve to achieve the necessary breaking strength according to the invention of at least 400 N, already serve as additional matrix materials.

If the dosage form according to the invention is intended for oral administration, they can preferably also have an enteric coating which dissolves as a function of the pH value of the release environment. Through this coating can be achieved in that the dosage form passes through the gastric tract undissolved and the active substance reaches the release only in the intestinal tract. Preferably, the enteric coating dissolves at a pH-value between 5 and 7.5.

Corresponding materials and methods for the controlled release of active ingredients and for applying enteric coating to the skilled artisan, for example, "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt N. Bauer, K. Lehmann, Hermann P . Osterwaldstraße, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers known. the corresponding literature description is hereby introduced as a reference and is part of the disclosure.

In the dosage forms according to the invention obtained, the breaking strength is determined using the measurement method mentioned, said different dosage forms of tablets are also tested.

To determine the breaking strength of the dosage form according to the invention are dosage forms, preferably tablets, having a diameter of 10 mm and a height of 5 mm.

These dosage forms, preferably tablets, method no. 2.9.8, according to the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143, 144. using the apparatus described below determines the breaking strength of the dosage form. The apparatus used for the measurement is a Zwick material tester "Zwick Z 2.5", material testing Fmax = 2.5 kN with a crosshead of max. 1150 mm, which is set by a configuration using a column and a spindle, a free clearance behind of 100 mm ., and a from 0.1 to 800 mm / min test speed adjustable and software. testControl There is a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, Fmax 1 kN, diameter 8 mm, class. 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18 (Zwick gross force Fmax 1.45 kN) used to measure (all apparatus from Zwick GmbH & Co. KG , Ulm, Germany) with the order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC 0050N. P01 for the force transducer, order no. BO 70000 S06 for the centering device.

4 shows the measurement of the breaking strength of a tablet, in particular the adjusting device used for this purpose ( 6 () Of the tablet 4 ) Before and during the measurement. For this, the tablet is ( 4 ) (Between the upper pressure plate 1 ) And the lower pressure plate ( 3 ) Of the device not shown for the application of force by means of two 2-part clamping devices, which (in each case with the upper and lower printing plate after adjustment of the necessary for receiving and centering the tablet to be measured distance 5 are not shown)) firmly connected (. (For adjusting the distance 5 ), The 2-part clamping devices in each case on the pressure plate on which they are mounted, are moved horizontally outwards or inwards. The reference numerals used relate solely to 4 ,

As resistant to breaking under a specific load, the tablets are classified, which have not broken but possibly plastic deformation of the tablet is made by the application of force.

In the following the invention is explained by examples. These explanations are merely exemplary and do not restrict the general inventive idea.

In a series of examples diltiazem hydrochloride, verapamil Hyddrochlorid carbamazepine and as active ingredients (substance (A)) were used.

Example 1:
All components were mixed in a tumbler. A tabletting tool with top punch, bottom punch and die for tablets with 10 mm diameter and a radius of curvature of 8 mm was heated in an oven at 80 ° C. By means of the heated tool in each case 300 mg of the powder mixture were pressed, wherein the pressing pressure for at least 15 s is maintained by clamping the tabletting tool in a vice.
The hardness of the tablets was determined according to the method specified with the stated apparatus. With a force of 500 N no break the tablets did.
The tablet could not be comminuted using a hammer. This was not possible with the aid of a mortar and pestle.
The in vitro release of the active ingredient from the preparation was determined in a paddle stirrer according to Pharm. Eur. (Paddle with sinker). The temperature of the release medium was 37 ° C and the rotational speed of the stirrer 50 min -1. At the beginning of the examination, each tablet was placed in each 900 ml of artificial gastric juice pH 1.2. After 30 minutes the pH was increased to 2.3 by addition of alkali, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The located one at a time in the dissolution medium released amount of the drug was measured spectrophotometrically at 236 nm in 2 mm cuvettes.
Example 2:
Analogously to Example 1 oblong tablets were produced with a diameter of 9 mm and a longitudinal length of 20 mm with the following composition:
The hardness of the tablets was determined according to the method specified with the stated apparatus. With a force of 500 N no break the tablets did.
The in vitro release of the drug was determined analogously to Example 1 (UV detection at 279 nm) and found to be:
Example 3:
Analogously to Example 1 round tablets were produced with a diameter of 20 mm the following composition:
The hardness of the tablets was determined according to the method specified with the stated apparatus. With a force of 500 N no break the tablets did.
The in vitro release of the drug was determined analogously to Example 1 (UV detection at 285 nm) and found to be:

Claims

Dosage form comprising - a physiologically active substance (A) with at least partially retarded release; - optionally one or more physiologically acceptable auxiliary substances (B); and - a synthetic or natural polymer (C); wherein the dosage form exhibits a breaking strength of at least 400 N.
Dosage form according to claim 1, characterized in that it contains no psychotropic active substances.
Dosage form according to claim 1 or 2, characterized in that it contains a natural, semisynthetic or synthetic wax (D).
Dosage form according to any of the preceding claims, characterized in that the substance (A) is a food supplement or a drug.
Dosage form according to any of the preceding claims, characterized in that it is in the form of a tablet.
Dosage form according to any of the preceding claims, characterized in that it is in multiparticulate form; preferably, optionally pressed or in the form of microtablets, micropellets, granules, spheroids, beads or pellets into tablets filled in capsules, is present.
Dosage form according to any of the preceding claims, characterized in that the polymer is selected (C) from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof, and mixtures thereof.
Dosage form according to claim 7, characterized in that the polymer (C) has a molecular weight of at least 0.5 10 6 g / mol, more preferably at least 1.0 10 6 g / mol and more preferably 1.0 10 6 to 15 10 6 g / mol.
Dosage form according to any of the preceding claims, characterized in that it comprises at least one wax (D) having a softening point of at least 50 ° C.
Dosage form according to claim 9, characterized in that the wax (D) Carnauba wax or bees wax.
Dosage form according to any of the preceding claims, characterized in that the substance (A) is in a sustained release matrix.
Dosage form according to claim 11, characterized in that the polymer (C) and / or the optional wax (D) serves as Retardmatrixmaterial.
Dosage form according to any of the preceding claims, characterized in that it releases under physiological conditions after 5 hours of not more than 99% of the substance (A).
Dosage form according to claim 13, characterized in that it does not contain either tramadol hydrochloride oxycodone hydrochloride.
Dosage form according to any of the preceding claims, characterized in that the substance (A) is a drug selected from the group consisting of agents for the treatment and prevention of diseases of the digestive system and metabolism; Agents for the treatment and prevention of diseases of the blood and blood-forming organs; Agents for the treatment and prevention of diseases of the cardiovascular system; Dermatological; Agents for the treatment and prevention of diseases of the genitourinary system and sex hormones; systemic hormone preparations exclusively sex hormones and insulins; Anti-infectives for systemic use; antineoplastic and immunomodulatory agents; Agents for the treatment and prevention of diseases of the muscles and the skeletal system; Agents for the treatment and prevention of diseases of the nervous system; antiparasitic agents, insecticides and repellents; Agents for the treatment and prevention of diseases of the respiratory tract; Agents for the treatment and prevention of diseases of the sense organs; General diet and radiotherapeutic agents.